Herpes simplex virus (HSV) is a common cause of infection, with about 60% of US adults seropositive for HSV-1 and 20% for HSV-2 [1]. Infection with either serotype can cause neurologic morbidity and mortality in susceptible populations, especially after neonatal transmission [2]. HSV infection is generally initiated at either mucosal or skin surfaces, and shedding from skin and mucosa after reactivation of latent virus is a primary mode of transmission [3, 4]. Infection of susceptible cells is initiated after binding of one of several specific cell surface receptors to viral ligands, with subsequent fusion of the viral envelope with the cell membrane and delivery of viral DNA into the cell [5, 6]. Although several viral proteins are capable of mediating attachment, binding of the gD glycoprotein to one of its receptors is required for subsequent membrane fusion and productive HSV infection. Cell surface receptors for gD include herpes virus entry mediator (HVEM), nectin-1 or -2, and specific sites in heparan sulfate [6]. HVEM is a member of the tumor necrosis factor (TNF) receptor superfamily of proteins [7]. HVEM is expressed in many tissues, but its natural function appears to be in regulating immune responses. Although lymphocytes are not thought to be significant targets of HSV infection, the known natural ligands of HVEM enhance or inhibit lymphocyte activation [8], suggesting that the gD-HVEM interaction could influence lymphocyte-mediated immunity to HSV. However, our recent data suggests that innate immune signaling initiated by epithelial cells is altered by the interaction of HSV with HVEM [9]. We do not have a mechanistic understanding of this effect, and our ongoing studies are directed at elucidating a mechanism. The purpose of this proposed study is to generate additional data on the influence ofthe HSV gD-HVEM interaction on the generation of early innate responses in keratinocytes, the first cells to encounter HSV after primary infection. The overall hypothesis is that signaling pathways downstream of HVEM are altered upon engagement with HSV, leading to an innate immune response that provides an initial advantage for viral replication. This study takes advantage of viral mutants in our laboratory which are deficient in their ability to engage HVEM for entry (described in [9] and [10]), and will add Skin Disease Research Center (SDRC) expertise in keratinocyte culture and histopathology.